Strong gender differences are well documented for many neural-motor diseases, yet, experimental work on motor systems rarely includes both genders and when it does, sex comparisons are not made. This gap is critical and will be addressed by the work in this proposal. The cerebellum is the master coordination center in the brain and its dysregulation produces many kinds of motor diseases. The ultimate goal of this research is to determine if mutations in sex chromosome genes play key roles in sexually dimorphic neurological motor disorders. The basis for the proposal is the observation that female mice, or mice of either sex with an XX sex chromosome complement, have more calbindin expression in the cerebellum than males or any XY individuals. Calbindin D28K is only present in the Purkinje cells, the only projection neurons in the cerebellum. This protein is linke with neuroprotection in the brain and reduced levels have been associated with many neurological diseases. The initial goal of this project is to determine if sex differences are the result of differences in numbers of Purkinje cells. The next question is to determine if there are sex differences dendritic structures in Purkinje cells. Finally we will determine if particular sub regions of the cerebellum are more sexually dimorphic than others. These goals will be accomplished with histological staining and morphometric analyses in addition to western blots and q RT-PCR. We will do all the studies in a mouse line allows separate analysis of sex chromosome complement and gonadal sex (i.e. ovaries and testes). Next, the genes that contribute to the sex differences will be revealed. This will be accomplished using a combination of engineered mouse models that enable cell-specific quantification of mRNA via gene expression microarray. Our hypothesis is that a sex chromosome gene(s) regulate calbindin and together these two factors modify Purkinje cell connections in a sexually dimorphic manner. This program offers a novel perspective on sex differences in cerebellar function based on sex chromosome genes; this will lead to innovations in diagnostics and interventions for patients with neurological motor diseases. PUBLIC HEALTH RELEVANCE: Neurological disorders strike an estimated 50 million Americans each year, and more of these patients are men than women. The research conducted in this program is specifically aimed at discovering the genetic bases for elevated vulnerability in men.